Pathophysiological role of cardiotrophin-1 in heart failure

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Cardiotrophin-1 (CT-1) is a potent cytokine that stimulates the assembly of sarcomeric units in series in cardiomyocytes through gp130 signaling, resulting in myocardial cell hypertrophy. We examined the role of CT-1 and gp130 system in the two rat models of congestive heart failure. First, we examined the expression of CT-1 and gp130 in a rat model of myocardial infarction. Progressive left ventricular dilatation and inadequate hypertrophy of the surviving myocardium were confirmed by echocardiography. The densitometric analysis of RT-PCR revealed a significant increase in CT-1 and gp130 mRNA levels compared with those of the sham-operated rats at 1, 3, 7, 14, 28 and 56 days post-infarct in both ventricles. The protein levels of CT-1 and gp130, determined by Western blot analysis, were significantly increased compared to those of sham-operated rats, and peaked in the acute stage and declned thereafter in the three regions described above. Immunohistochemical staining showed that CT-1 … More and gp130-immunoreactivities were detected in cardiomyocytes and fibroblast-like cells. An augmented CT-1 and gp130 system thus seems to play an important role during ventricular remodeling after myocardial infarction. Secondly, we examined the expression of CT-1 and gp130 in Dahl salt-sensitive (DS) rats with a high-salt diet which showed a distinct transition from left ventricular hypertrophy (LVH) to congestive heart failure (CHF). The expression levels of CT-1 were significantly increased at the CHF stage compared with the LVH stage and age-matched Dahl salt-resistant (DR) rats (n=6 for each group). gp130 mRNA and protein levels DS rats at 11 and 17 weeks were significantly increased compared with age-matched DR rats. The isolated myocyte length of DS rats at 17 weeks was the longest among the 4 groups of rats. The left ventricular end-diastolic dimension (LVDd) of DS rats was significantly increased at the CHF stage. There was a significant correlation between the CT-1 protein level and LVDd. CT-1 may play a role in ventricular remodeling during transition from LVH to CHF in the rat hypertensive model. These findings in the two heart failure models strongly suggest that CT-1 plays a central role in the ventricular dilatation in heart failure. Less